Process for preparing heterocyclic tertiary amines



United States Patent "O fili ce 3,163,651 PROCESS nonranraansormrnnocvcrrc TERTIARY AMINES Augusto egre and Rene Viterbo,Naples, Italy, assignors to S.p.A. Farmochimica Cutolo -Calosi, Naples,Italy, a company of Italy e N Drawing. Filed May 23, 1961, ser. No.111,903

Claims priority,application Italy, .Oct. 15,1957,"

. 14,871/57, 14,875/57 12 Claims. (Cl. 260-293) This invention relatesto a'method for preparing heterocyclic tertiary amines. This applicationis a continuationin part of our co-pending application Serial Nos. 7 65,288 and 765,289, both filed on October 6, 1958, and both now abandoned.

The importance of organic substances containing tertiary amino groups,and in particular heterocyclic-tertiary amines is universallyacknowledged. Particularly, such tertiary amines are members of, orintermediates for the broad class of alkaloids which has found manyapplications in the therapeutical field. Y

General methods for the synthesis of tertiary amines have therefore beenelaborated and are used in large number.

Among the various methods known in the art, one is the simple andeconomical'process which comprisesreacting primaryfamine such as anilineunder substantially anhydrous conditions and in the presence of anelementary alkali metal or an alkali metal hydride as cataylst at atemperature of about 200 C. and at a pressure of about 800 to 1000atmospheres with an unsaturated acyclic hydrocarbon such as ethylene.

Further industrially applicable processes involve the reduction ofnitriles, by Curtius or Hofmann degradation and many others.

Another theoretically possible route is the following:

Tertiary amides have been obtained by the well known I aminolysisdescribed, for instanceby Fieser & Fieser, Organic Chemistry ,(1944),page 183, by reacting sec-j ondary unoxidized cyclic amines such aspiperidine with the alkyl esters of unsubstituted saturated aliphaticcarboXylic acids, such as methyl acetate. However, at 25 C., thereactivity of the secondaryamines in aminolysis is so low that thisreaction does not'lend itself to industrial use. 'Thus the rate constantfor; reaction rates of 10% completion between piperidine and methylacetate in methanol as solvent is only 0=47 X 10 while in .the.

presence of sodium methylate as catalyst in the solvent, it is stillonly 5.2 10- liters per mole per hour. After.

10% completion the constant decreases even further. (Baltzly andco-workers, J.A.C.S., 72 414941152 (1950).) V j? The conversion oftertiary amides to the corresponding tertiary amines having the samenumber of carbon atoms has been carried out with lithium aluminumhydride as the hydrogenation catalyst (Krajk'eman, ManufacturingChemist, XXII, 4, page 15 0), In viewof the unsatisfactory yields of thearninolysis of 'ester with secondary amines, this route has not attainedpractical value in-the production of tertiary amines.

It is an object of our invention to provide a novel process for theproduction of heterocyclic tertiary amines which uses readily availablestarting materials, while avoiding the high temperatures and pressuresrequired by the first-mentioned knownprocess and other drawbacks. suchas more limited availability of the starting materials and/or lowreaction rates of the other known processes.

'It is a further object of our invention-to provide atory yields.

1 3,163,651 Patented Dec, 29,1954

available heterocyclic secondary amines such as pyrrolidine andpiperidine by condensation, in an aminolysis type reaction, with thealkyl esters of unsubstituted saturated aliphatic carboxylic acids andwith the alkyl esters of aromatic acids such as benzoic acid, in thepresence of a simultaneously condensing and hydrogenating catalyst, inthe reaction mixture. j J 1 f We have further found that alkali metalaluminum. hydrides and particularly lithium aluminum hydride act as suchcondensanon-hydrogenation catalysts. 1 The method of the presentinvention therefore comprises,in the first'line, treating a cyclicsecondaryamine the nitrogen atom of which is included in the ring, andpreferably an amine of the aforesaid type in which all other atoms ofthe ring are carbon atoms, with an ester of solvents, in particular thealcohols, and among the latter the glycols, which catalyze the reactionbetween the ester and the secondary amine somewhat as has been mentionedhereinb'efore, such catalytic etfect is not sufiicient to obtainsatisfactory yields. No alkylation of cyclic secondary amines withesters of carboxylic acids (as potential alkylating agents) in thepresence of lithium aluminum hydride as reducing and condensing agent,has been known in the past.

If the above-defined two reactants are reacted with each other underotherwise identical conditions, but in the total absence of lithiumaluminum hydride, thestarting materials are quantitatively recovered.This demonstrates that LiAlH, is necessary during the reaction not onlyas a reducing agent, for in that event, the corresponding amide and.alcohol would be recovered, but also a condensing agent.

' The. above mentioned cycloaliphatic groups contain from two to sixcarbon atoms in'the ring and the aromatic; groups are five or sixmembered rings exclusive of carbon atoms and are preferably mononuclear.V V Accordingto another preferred mode of carrying out the method of ourinventionQa lactam is treatedwith a carboxylic acidester in the presenceof lithium aluminum hydride and a mixture is obtained wherefrom acyclic" tertiary amine'is isolated. When the lactam group and thecarboxylic'acid ester group are present in the same molecule, there isisolated from the resultingmixture a bicyclic tertiary amine wherein anovel ring is formed and closed on the nitrogen atom of the lactam.

This mode of carrying out our invention thus has the feature of startingfrom lactam and carboxylic acid esters to obtain teritiary amines, thenitrogen atom of which belongs to a ring, having the above-statedgeneral formula wherein R, R and It have the above-given definitions. Ifa solution of a lactam, for instance u-piperidone in a suitable organicsolvent and of a carboxylic acid ester, for instance the ethyl ester ofacetic acid, is reacted with lithium aluminum hydride (LiA1H a mixtureis obtained wherefrom a cyclic tertiary amine is recovered. The reactionmay be set out in the general terms:.

Lactams are well known to be internally condensed amides of 'y-, 6-, 6-,and higher saturated aliphatic carboxylic amides.

Typical examples are:

'y-Amino butyro-lactam fi-Amino-valero-lactam (oz-piperidone)e-Amino-capro-lactam Similar lactams are those derived from 'y (6)-aminosuberic acid andsimilar dicarboxylic saturated aliphatic acids. Theselactams are readily accessible and the caprolactam is manufacturedindustrially on a large scale.

In the particular case hereinbefore disclosed, starting froma-piperidone and ethyl acetate, in the presence of lithium aluminumhydride, N-ethyl-piperidine will be obtained. The reaction may bedescribed by the following formula:

E1 H2 I! I I CH3COC3H5 LiAlHi O=C CH2 a-piperidone ethyl acetate f31120- CH ([2 OzHsOH Hz 2 LiAlOg i CHQCH: N-ethyl-plperidlne ethanol Ifthe benzyl esterof benzoic acid is substituted by the ethyl ester ofacetic acid N-benzyl piperidine will be obtained. The reaction may herepresented by the following formula:

'a-pip'erldone benzylb'enzoate N N-benzyl-plperidlne benzyl alcohol Thesynthesis of the tertiary amines by the method of the present inventioncan also be applied if the lactam group and the carboxylic ester groupbelong to the same molecule. In this case a cyclization occurs on thenitrogen atom as exemplified here-after.

If the methyl ester of the 1- 5 lactam of S-aminosuberic acid is treatedwith lithium aluminum hydride, a mixture is obtained, wherefromdelta-coniceine, a natural bicyclic alkaloid, is isolated. The followingformula repof our method are carried out in the liquid phase, with asuitable anhydrous organic solvent free from hydroxyl groups such asdiethyl ether, at a temperature of about 20 to 40 C. and preferably 35to 37 C. and under atmospheric pressure.

In the above mentioned reactions lithium aluminum hydride acts both as areducing agent and as a condensing agent. It would be possible to think,at first sight, that the lithium aluminum hydride acts only as areducing agent on the lactam function forming a secondary amine whichwould undergo a condensation with the ester group without anyintervention of lithium aluminum hydride. The amine group so formedwould be then reduced by lithium aluminum hydride to a tertiary amine.This however is not true. In fact if a secondary amine is treated with acarboxylic ester under the same mild conditions as hereinbeforedescribed but in the absence of lithium aluminum hydride, the startingmaterials are quantitatively recovered. Thus it is demonstrated that inthe reaction of a lactam with a carboxylic acid ester in the presence oflithium aluminum hydride, the latter acts as a reducing agent as well asa condensing agent.

The reducing action of the lithium aluminum hydride is well known.However, its action as a condensing agent between lactams and esters ofcarboxylic acid is new.

In both modes of carrying out the method of our invention in practice,the solvent in which the reaction takes place, and ,in which thecatalyst is suspended must be inert; dialkyl ethers are preferred, andamong these diethyl ether is the most easily available solvent.

The-last described synthesis of bicyclic tertiary amines in which atleast the nitrogen atom and one carbon atom are common to both rings, isof particular importance in the synthesis of alkaloid structures.

The starting compounds in this type of syntheses according to theinvention are especially the mono-lactams of dicarboxylic saturatedaliphatic amino-acids wherein the amino group is in -position or evenfarther removed irom the carboxylic acid group with which it forms thelactam. The other carboxylic acid group is esterified before the lactamis formed;

Processes tor the preparation of such lactams are described, forinstance,.in R. E. Eldorfield, Heterocyclic Compounds, vol. I, page 651,John Wiley and Sons, New York, 1950. p

In these syntheses lithium aluminum hydride acts simultaneously as acondensation, cyclization and reducing catalyst.

The present invention will be described hereinafter with reference tosome typical examples.

EXAMPLE 1 N-Ethyl-Pyrrolidine HzC---CH: 2 I 2CH3COCgH5 LiA1H4 H: /CH:

pyrrolidlna ethyl acetate HzC-'CH: 2 I (5 ZCzHsOH LiAlOg H2O H2 (IJHP CH3 N-ethyl-pyrrolidine ethanol An ether solution containing 9.5 grams ofpyrrolidine and 8.8 grams of acetic acid ethyl ester is slowly added toa suspension of 3.8 grams of lithium aluminum hydride in 300 cc. ofethyl ether. During the reaction, the mixture is maintained at about 35C. under atmospheric pressure. At the end of the reaction after aboutsixty minutes, the excess of lithium aluminum hydride is destroyed byadding water, and the mixture is then subjected to fractionateddistillation. 2.815 grams of N-ethylpyrr-olidine are isolated, B.P. 96C./760 mm. Hg.

Picrate, M.P. 180-182" C.

Analysis.-Calculated for C12H16N4O7: c=43.90%;

H=4.92%; N=17.07%. Found: C=43.82%;H=5.25%;

I CHrCHs V N-ethyl-plperidine ethanol An ether solution containing 8.55grams of piperidine and 8.8 grams of acetic acid ethyl ester is slowlyadded to a suspension containing 3.8 grams of lithium aluminum hydridein ethyl ether, and further treated as described in Example 1. v

3.33 grams of N-ethyl-piperidine are isolated, B.P. l128 C./760 mm. Hg.The picrate shows an M.P. 165167 C. I

6 Analysis-Calculated for C H gO N C=45.60%; H 5.31%; N 16.37%. Found: C45.40%; H=5.39%; N=l6.52%.

EXAMPLE 3 N -Benzyl-Pi periqlin'e 320 oln F0431? 2 1 LiAlH4 Hz /CH2 V eplperldlne benzyl benzoate H20 7 CH1 -Q N-benzyl-piperidine benzylalcohol In an ether solution of 2.6 grams of piperidine are suspended0.3 gram of lithium aluminum hydride, and an ether solution containing7.8 grams of benzoic acid benzylic ester is slowly added. During theensuing reaction the temperature is held at about 3'5 to 37 C. At theend of the reaction, after about sixty minutes, 0.6 gram of lithiumaluminum hydride are added, and the mixture is left standing for sixtyminutes. The excess of lithium aluminum hydride is thendestroyed byaddition of water, and the mixture is subjected to fractionateddistillation. Thereby, 2.6 grams of N-benzyl-piperidine are isolated;B.P. 102-l09 C./ 15 mm. Hg. Picrate; M.P. l76-178 C.

Analysis.Calculated for C H O N C, 53.46%; H,

4.99%; N, 13.86%. Found: C, 53.42%; H, 5.15%; N,

EXAMPLE 4 Preparation of N-Ethyl-Piperidine From Lactam To 4.1 grams ofa piperidone dissolved in 50 cc. of anhydrous ethyl ether and 2.7 gramsof acetic acid ethyl ester there are slowly added 2.2 grams of lithiumaluminum hydride and the reaction mixture is held under atmosphericpressure at a temperature of 37 C. At the end of the reaction, afterabout sixty minutes, the excess of lithium aluminum hydride is destroyedby adding water and the mixture is then subjected to fractionateddistillation whereby there are recovered 1.6 grams ofN-ethy-l-piperidine, B.P. 128 C ./760 mm. Hg. Picrate, M.P. 165-167 C.

Analysis.Ca1culated forC H O N H=5.31%; N=16.37%. 5.31%; N=16.49%.

Found: C=45.35%; H

EXAMPLE 5 Preparation of the N -Ben z yl-Piperidine 4.1 grams ofa-piperidone dissolved in 50 cc. of ethyl ether and 5.7 grams of benzoicacid benzylic ester also dissolved in 50 cc. of anhydrous ethyl ether,are treated with 2.2 grams of lithium aluminum hydride in the same 1.44grams of N- Delta-Coniceine 4 grams of methyl ester of the 1 5 lactani'ofV S-amino suberic acid (boiling point l56'-162 C./0.5 mm. Hg) aredissolved in cc. of anhydrous ethyl ether and 7 added to a suspension ofgrams of lithium aluminum hydride in 500 cc. of anhydrous ethyl ether.The mixture is treated as described in Example 4. 0.447 gram ofdelta-coniceine are obtained, B.P. 50 C./l5 mm. Hg.

Analysis-Calculated for C H N: C=76.74%; H: 12.08%;N=11.19 Found:C='76.58%;H=12.02%; N= 1l.00%.

Picrate: M.P. 226-227 C.

Analysis.-Calculated for C H O N C=47.45%; H=,5.12%; N=15.81%. Found:C=47.58%; H: 5.40%; N=15.92%.

While some specific embodiments of this invention have been described indetail to illustrate the application of the invention principles, itwill be understood that the invention may be embodied otherwise withoutdeparting from such principles.

We claim:

1. The method described in claim 11, wherein the alcohol moiety of theester is an alkyl group having from two to seven carbon atoms.

2. The method described in claim 11, wherein the heterocyclic compoundis a-piperidone and the ester is benzyl benzoate.

3. The method described in claim 11, wherein the heterocyclic compoundis u-piperidone and the ester is methyl acetate. v

4. The method described in claim 11 wherein the reaction mixture isheated to a temperature of 37 to 39 C.

5. The method described in claim 11', wherein the inert solvent is anether.

6. The method described in claim 11, wherein the inert solvent isdiethyl ether.

7. The method according to claim 12 wherein the lactam 'carboxylic acidester is the methyl ester of the 1 5 lactam of S-arhino-suberic acid.

8. A process as described in claim 11 .wherein the heterocyclic compoundis' pyrjrolidi'ne and the ester is ethyl acetate.

9. A process as described in claim 11 wherein the heterocyclic compoundis piperidine and the ester is ethyl acetate.

10.'A process as described in claim -11 wherein the heterocycliccompound is piperidine and the ester is benzyl benzoate.

11. Processfor producing a tertiary amine of the formula wherein n is aninteger from 1. -to 4, each R is a member selected from the groupconsisting of H and lower alkyl, and R is a member selected from thegroup consisting of lower alkyl, cycloalkyl, and monnuclear aromatichydrocarbon, which comprises mixing a heterocyclic compound of theformula i wherein n is an integer of from 1 to 4, each R is a memberselected from the group consisting of H and lower alkyl, and CY is amember selected from the group consisting of CH and C= O; with (a) anester selected from the group consisting of lower alkyl and cycloalkylesters of lower allranoic acids, 'cycoalkanoic acids, and mononucleararomatic hydrocarbon 'carboxylic acids, (b) lithium alur ninum hydrideand (c) inert organic solvent at a temperatureof from 20 to 40 C.

12. Process for producing a teritary amine of the formula car-(0 2).

Cfiz wherein n is an integer from 1 to 2, and R is lower alkylene, whichcomprises mixing cyclic lactam of the formula wherein n is an integerfrom 1 to 2 and each of R and R is lower alkyl, with (a) lithiumaluminum hydride and (b) an inert organic solvent at a temperature offrom 20 to 40 C.

References Cited by the Examiner Baltzy et a l.: Journal of the AmericanChemical Society, vol. 72, pages 4149-4152 (1950) Arnett et al.: Journalof the American Chemical Society, vol. 73, pages 5393-5395.

Barry et -aI.: Proceedings of the Royal Irish Academy, vol. -B, pages137-139 (1953).

Krajkeman: Manufacturing Chemist, vol. 22 [No. 4], pages 149-150 (1951).

Richters Organic Chemistry, Heterocyclic Compounds, Free Radicals(Textbook), vol. 4, pages 3-5 (1947 Edition), Elsevjer Publishing Co.,Inc., New York, NY.

IRVING MARCUS, Primary Examiner.

WALTER A. MODANCE, Examiner.

2. THE METHOD DESCRIBED IN CLAIM 11, WHEREIN THE HETEROCYCLIC COMPOUNDIS A-PIPERIDONE AND THE ESTER IS BENZYL BENZOATE.
 11. PROCESS FORPRODUCING A TERTIARY AMINE OF THE FORMULA